The dopamine transporter is a principal target of cocaine in the brain. The overall objectives of the research are to investigate the therapeutic potential of novel drugs that bind the transporter with higher affinity than does cocaine. We recently reported a new series of compounds targeted to transporters, that unlike all current transporter drugs, contain no amine nitrogen in their structure. Among the most potent in this series was O-913, (2--carbomethoxy-3-(3,4dichlorophenyl)-8-oxabicyclo[3.2.1]octane) which bound with high affinity to the dopamine transporter in cynomolgus monkey striatum (IC50 3.08 q 0.07 nM) or human putamen (IC50 4.53 q1.58) and is a potent inhibitor of dopamine transport in COS-7 cells expressing the human dopamine transporter (IC50 5.9 q 0.9 nM). To investigate whether O-913 produces subjective effects similar to those produced by monoamine transporter inhibitors, O-913 was tested in squirrel monkeys trained to discriminate cocaine from vehicle under a two-lever choice procedure. O-913 engendered dose-related increases in the proportion of responses directed to the cocaine-associated lever, and full substitution for cocaine (> 90% cocaine-appropriate responding) was achieved at 1 mg/kg (n = 4). The results indicate that the aryloxatropane O-913 enters the brain and produces cocaine-like discriminative stimulus effects. These studies indicate that nonamine dopamine transport inhibitors cross the blood-brain barrier to produce behavioral effects similar to their amine nitrogen-bearing counterparts. Together with other biochemical, pharmacological and imaging data, these results suggest that nonamines have the same potential and drug therapies as do monoaminergic drugs. Further evaluation of this class of compounds is ongoing. Madras BK, Pristupa ZB, Niznik HB, Liang AY, Meltzer PC. Novel compounds reveal that nitrogen-based drugs are not essential for